PACAP in Hypothalamic Regulation of Sleep and Circadian Rhythm: Importance for Headache Philip R
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Holland et al. The Journal of Headache and Pain (2018) 19:20 The Journal of Headache https://doi.org/10.1186/s10194-018-0844-4 and Pain REVIEWARTICLE Open Access PACAP in hypothalamic regulation of sleep and circadian rhythm: importance for headache Philip R. Holland1*, Mads Barloese2* and Jan Fahrenkrug3 Abstract The interaction between sleep and primary headaches has gained considerable interest due to their strong, bidirectional, clinical relationship. Several primary headaches demonstrate either a circadian/circannual rhythmicity in attack onset or are directly associated with sleep itself. Migraine and cluster headache both show distinct attack patterns and while the underlying mechanisms of this circadian variation in attack onset remain to be fully explored, recent evidence points to clear physiological, anatomical and genetic points of convergence. The hypothalamus has emerged as a key brain area in several headache disorders including migraine and cluster headache. It is involved in homeostatic regulation, including pain processing and sleep regulation, enabling appropriate physiological responses to diverse stimuli. It is also a key integrator of circadian entrainment to light, in part regulated by pituitary adenylate cyclase-activating peptide (PACAP). With its established role in experimental headache research the peptide has been extensively studied in relation to headache in both humans and animals, however, there are only few studies investigating its effect on sleep in humans. Given its prominent role in circadian entrainment, established in preclinical research, and the ability of exogenous PACAP to trigger attacks experimentally, further research is very much warranted. The current review will focus on the role of the hypothalamus in the regulation of sleep-wake and circadian rhythms and provide suggestions for the future direction of such research, with a particular focus on PACAP. Keywords: Migraine, Cluster headache, Circadian, Circannual, Hypothalamus, Pituitary adenylate cyclase-activating peptide Background disturbances [13, 14] and neuroimaging data suppor- Primary headache disorders represent a group of diverse ting abnormal hypothalamic activation in several pri- neurological attack forms that present with varying mary headache disorders [2, 4–6, 8, 15]thereisan intensity, duration, frequency and associated symptoms unmet need to develop novel mechanistic insight that [1]. Despite these underlying differences the hypothal- may herald novel therapeutic strategies. In particular pitu- amus has emerged as a critical component of several itary adenylate cyclase-activating peptide (PACAP) has attack forms, including migraine [2–5]andcluster emerged as a key neuropeptide involved in migraines and, headache [6–8].Thehypothalamusisakeyregulator as a parasympathetic and hypothalamic signaling of homeostatic mechanisms including sleep-wake molecule, that may be involved in cluster headache. cycles that are under circadian regulation [9]. Given PACAP is known to trigger migraine [16, 17]insuscep- the circadian and circannual nature of several attack tible individuals, plays a key role in hypothalamic circa- forms [10–12], the clinical association with sleep dian entrainment to light [18] and is the subject of significant interest as a potential therapeutic target for mi- * Correspondence: [email protected]; graine and cluster headache [19, 20]. As such, the current [email protected] review will focus on the potential regulation of sleep and 1Department of Basic and Clinical Neuroscience, Headache Group, Institute circadian mechanisms in primary headache disorders with of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK a particular focus on the regulation and future therapeutic 2Department of Clinical Physiology, Nuclear Medicine and PET, 70590 potential of modulating PACAP signaling. Rigshospitalet, Copenhagen, Denmark Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Holland et al. The Journal of Headache and Pain (2018) 19:20 Page 2 of 8 Introduction regulated by at least two divergent mechanisms inclu- The ability to adapt to external environmental condi- ding circadian and homeostatic sleep pressure. This ele- tions is a fundamental principle for the survival of an gant regulatory mechanism allows the body to respond organism. As such several systems have evolved that per- to “sleep need” via the accumulation of an endogenous mit homeostatic regulation to internal and external cues, somnogens (e.g. Adenosine) on the background of a facilitating appropriate physiological responses. These circadian influence that entrains sleep-wake cycles to are most evident in the daily regulation of sleep-wake external cues such as seasonal light-dark patterns, for re- cycles with its circa 24-h rhythmicity (circadian), but view see [9]. The neuroanatomical basis for sleep was also include circannual (yearly), infradian (> day) and ul- initially postulated in response to a wave of “encephalitis tradian (< day, but > one hour) rhythms. Sleep itself is lethargica” with the neurologist Von Economo detailing generally dissected into wakefulness, non-rapid eye the presence of lesions in the border of the midbrain movement (NREM), and paradoxical or rapid eye move- and diencephalon responsible for this excessive sleepi- ment (REM) sleep. Encephalographically, REM sleep and ness [23] and thus forming the basis for our current wakefulness are indistinguishable with fast, low ampli- understanding of arousal networks (see Fig. 1). tude, desynchronized oscillations, whereas NREM sleep Complimentary observations in patients presenting with stages I-III are characterized by increasingly lower fre- insomnia highlighted lesions within the lateral hypothal- quencies of synchronized cortical activity. The different amic area, with subsequent studies identifying specific stages of sleep are precisely regulated, complex mecha- cell groups including the ventrolateral preoptic area nisms ensuring their consolidation at specific times (for (VLPO) that act to promote sleep [24] and inhibit review see [21]), timely progression and avoidance of arousal networks [25]. A further seismic step in our un- intermediary stages. derstanding of the regulation of sleep-wake cycles came While a complete understanding of the function of with the proposal of a “flip-flop” switch; whereby hypo- sleep remains to be fully characterized it clearly has a thalamic orexinergic synthesizing neurons act to restorative effect on the brain [22]. It is proposed to be reinforce the ascending arousal networks during a b c Fig. 1 Mechanisms regulating sleep wake modulation. a. Orexinergic neurons originating in the lateral hypothalamus (LH; Green) send excitatory projections to several brainstem nuclei that act to promote arousal. Ascending monoaminergic projections (purple) from the noradrenergic locus coeruleus (LC), glutamaterigic parabrachial (PB) and pedunculopontine (PPT), serotoninergic dorsal raphe (DR), dopaminergic ventral periaqueductal grey (vPAG), tuberomammillary nuceus (TMN) and GABAergic and cholinergic neurons in the basal forebrain (BF) diffusely innervate the cerebral cortex to promote arousal. There are also cholinergic projections (Blue) from the laterodorsal tegmental nuclei (LDT) and PPT nuclei that project to the thalamus to promote arousal. b. GABAergic ventrolateral preoptic (VLPO) neurons (Brown) act to inhibit the majority of the arousal nuclei, including LH orexinergic neurons to promote sleep. c. Homeostatic sleep pressure (Blue line) increases through wakefulness, likely via the accumulation of endogenous somnogens such as adenosine that excites VLPO neurons to promote sleep. This is combined with circadian sleep regulation (Red line) to create a balanced sleep wake cycle that is entrained to external environmental conditions. The circadian component is in part dependent on pituitary adenylate cyclase-activating peptide signalling within the hypothalamic suprachiasmatic nucleus as demonstrated by preclinical research Holland et al. The Journal of Headache and Pain (2018) 19:20 Page 3 of 8 wakefulness and are reciprocally inhibited in conjunction Sleep and circadian rhythms in headache with the ascending arousal nuclei by the VLPO during The interaction between sleep and headache has gained sleep [26]. The importance of these neurons in the considerable interest due to a strong but complex clin- regulation of arousal is evident in the devastating conse- ical relationship. This is evidenced from clinical and quences their loss has on patients suffering from narco- population studies demonstrating a high penetrance of lepsy [27]. sleep problems or manifest sleep disorders in headache Given the complex clinical relationship between circa- [44] and an ever increasing number of sophisticated dian/sleep regulation and headache, their shared physio- sleep studies [45–47] that point to several major points logical and neuroanatomical basis (see Fig. 1 and reviewed of physiological and neuroanatomical overlap (for review in [9, 28]), the emerging role